The Rosetta software suite for macromolecular modeling, docking, and design is widely used in pharmaceutical, industrial, academic, non-profit, and government laboratories. Despite its broad modeling capabilities, Rosetta remains consistently among leading software suites when compared to other methods created for highly specialized protein modeling and design tasks. Developed for over two decades by a global community of over 60 laboratories, Rosetta has undergone multiple refactorings, and now comprises over three million lines of code. Here we discuss methods developed in the last five years in Rosetta, involving the latest protocols for structure prediction; protein-protein and protein-small molecule docking; protein structure and interface design; loop modeling; the incorporation of various types of experimental data; modeling of peptides, antibodies and proteins in the immune system, nucleic acids, non-standard chemistries, carbohydrates, and membrane proteins. We briefly discuss improvements to the energy function, user interfaces, and usability of the software. Rosetta is available at www.rosettacommons.org.
De novo protein design holds promise for creating small
stable proteins with shapes customized to bind therapeutic targets. We describe
a massively parallel approach for designing, manufacturing and screening
mini-protein binders, integrating large-scale computational design,
oligonucleotide synthesis, yeast display screening and next-generation
sequencing. We designed and tested 22,660 mini-proteins of 37–43
residues that target influenza haemagglutinin and botulinum neurotoxin B, along
with 6,286 control sequences to probe contributions to folding and binding, and
identified 2,618 high-affinity binders. Comparison of the binding and
non-binding design sets, which are two orders of magnitude larger than any
previously investigated, enabled the evaluation and improvement of the
computational model. Biophysical characterization of a subset of the binder
designs showed that they are extremely stable and, unlike antibodies, do not
lose activity after exposure to high temperatures. The designs elicit little or
no immune response and provide potent prophylactic and therapeutic protection
against influenza, even after extensive repeated dosing.
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